title: Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones.
abstract: A series of azetidin-2-ones substituted at positions 1, 3 and 4 of the azetidinone ring scaffold were synthesised and evaluated for antiproliferative, cytotoxic and tubulin-binding activity. In these compounds, the cis double bond of the vascular targeting agent combretastatin A-4 is replaced with the azetidinone ring in order to enhance the antiproliferative effects displayed by combretastatin A-4 and prevent the cis/trans isomerisation that is associated with inactivation of combretastatin A-4. The series of azetidinones was synthetically accessible via the Staudinger and Reformatsky reactions. Of a diverse range of heterocyclic derivatives, 3-(2-thienyl) analogue 28 and 3-(3-thienyl) analogue 29 displayed the highest potency in human MCF-7 breast cancer cells with IC(50) values of 7 nM and 10nM, respectively, comparable to combretastatin A-4. Compounds from this series also exhibited potent activity in MDA-MB-231 breast cancer cells and in the NCI60 cell line panel. No significant toxicity was observed in normal murine breast epithelial cells. The presence of larger, bulkier groups at the 3-position, for example, 3-naphthyl derivative 21 and 3-benzothienyl derivative 26, resulted in relatively lower antiproliferative activity in the micromolar range. Tubulin-binding studies of 28 (IC(50)=1.37 μM) confirmed that the molecular target of this series of compounds is tubulin. These novel 3-(thienyl) β-lactam antiproliferative agents are useful scaffolds for the development of tubulin-targeting drugs.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland. oboyleni@tcd.ie
authors.forename: Niamh M
authors.initials: NM
authors.lastname: O'Boyle
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Greene
authors.forename: Orla
authors.initials: O
authors.lastname: Bergin
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Fichet
authors.forename: Thomas
authors.initials: T
authors.lastname: McCabe
authors.forename: David G
authors.initials: DG
authors.lastname: Lloyd
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Meegan
mesh_terms: D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011247:Pregnancy; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C116379:2-azetidinone; D001384:Azetidines; D014404:Tubulin; D047090:beta-Lactams